16-2109556-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001009944.3(PKD1):c.5611G>A(p.Ala1871Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,611,596 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_001009944.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.5611G>A | p.Ala1871Thr | missense_variant | 15/46 | ENST00000262304.9 | NP_001009944.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00434 AC: 661AN: 152234Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00425 AC: 1044AN: 245780Hom.: 4 AF XY: 0.00449 AC XY: 602AN XY: 133936
GnomAD4 exome AF: 0.00671 AC: 9789AN: 1459244Hom.: 54 Cov.: 34 AF XY: 0.00663 AC XY: 4810AN XY: 725874
GnomAD4 genome AF: 0.00434 AC: 661AN: 152352Hom.: 1 Cov.: 33 AF XY: 0.00391 AC XY: 291AN XY: 74508
ClinVar
Submissions by phenotype
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2021 | This variant is associated with the following publications: (PMID: 17582161, 22608885, 30647506) - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | PKD1: BP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 25, 2019 | - - |
Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Polycystic kidney disease, adult type Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2019 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Ala1871Thr variant was identified in 2 of 460 proband chromosomes (frequency: 0.004) from individuals or families with ADPKD, being classified as a polymorphism/likely neutral (Rossetti 2007, Rossetti 2012, Tan 2009, Tan 2014). The variant was identified in dbSNP (ID: rs144137200) as “With Likely benign allele”, Clinvitae and ClinVar (classification likely benign, submitter Prevention Genetics), and the ADPKD Mutation Database (classification likely neutral); but was not identified in GeneInsight-COGR, MutDB, PKD1-LOVD, and PKD1-LOVD 3.0. This variant was also identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002), HAPMAP-EUR in 3 of 1006 chromosomes (frequency: 0.003)/-AMR in 3 of 694 chromosomes (frequency: 0.0043)/-SAS in 2 of 978 chromosomes (frequency: 0.002), the NHLBI GO Exome Sequencing Project in 49 of 8560 European American alleles (freq. 0.006) and in 6 of 4374 African American alleles (freq. 0.001), the genome Aggregation Database (beta, October 19th 2016) in 1142 (4 homozygous) of 272522 chromosomes (freq. 0.004) and in the Exome Aggregation Consortium database (August 8th 2016) 485 (4 homozygous) of 104730 chromosomes (freq. 0.0046) in the following populations: European (Non-Finnish) in 364 of 57774 chromosomes (freq. 006), South Asian in 84 of 15042 chromosomes (freq. 006), Other in 4 of 732 chromosomes (freq. 006), Latino in 20 of 10302 chromosomes (freq. 002), African in 10 of 8320 chromosomes (freq. 001), and in European (Finnish) in 3 of 4634 chromosomes (freq. 0006); but was not seen in East Asian; increasing the likelihood this could be a low frequency benign variant. In addition we cannot be certain that data from control databases is specific to PKD1 and not from one of the six PKD1 pseudogenes. The p.Ala1871 residue is not conserved in mammals and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
PKD1-related disorder Benign:1
Benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 22, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at